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Welcome to Northeastern University’s science and research blog. We call it iNSolution because that’s what our faculty and student researchers are in the business of—finding solutions to societal problems while simultaneously contributing to the fundamental knowledge base of their respective fields.

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Smarten up

Assis­tant pro­fessor Ganesh Thakur’s research could lead to a drug that has the cog­ni­tive ben­e­fits of nico­tine without its neg­a­tive side effects. Photo via Thinkstock.

Here’s a simple expla­na­tion for how many addic­tions work: you con­sume a chem­ical compound–through inges­tion, inhala­tion, whatever–that looks or works a lot like another com­pound that’s nat­u­rally present in your body. The nat­u­rally occur­ring, or “endoge­nous,” com­pound hap­pens to be one that binds to their spe­cific receptor in your brain that trig­gers a whole down­stream slew of events, such as increase in dopamine levels, that give you some kind of happy feeling, which you want to have again and again.

With nico­tine, the story is a little different…or at least a little more nuanced. Yes, there’s the pri­mary addiction-​​promoting receptor (it’s called α4β2 nico­tinic acetyl­choline receptor, or nAChR), but another receptor (α7 nAChR) also plays a role. This is the receptor that is respon­sible for the cog­ni­tion enhancing effects that one expe­ri­ences when they smoke cig­a­rettes (Really? Cig­a­rettes make us smarter? Youbetcha.)

While the dose of smarts isn’t the most addic­tive part of nico­tine, it cer­tainly increases a person’s desire for more, said North­eastern assis­tant pro­fessor of phar­ma­ceu­tical sci­encesGanesh Thakur. He’s working on devel­oping alter­na­tives to things like mar­i­juana (as dis­cussed in this news@Northesatern story) and nico­tine that have the same ben­e­fits without the neg­a­tive side effects.

In one project, he and his team have cre­ated a com­pound that they’ve shown to be neu­ro­pro­tec­tive in animal studies: Older ani­mals that had already demon­strated dimin­ished cog­ni­tive capacity expe­ri­enced improved memory and cog­ni­tion when they took Thakur’s drug.

The drug works roughly the same way as other drugs he’s devel­oping to more safely reap the ben­e­fits of the mar­i­juana happy-​​making receptor, CB1. There, the idea is to target other recep­tors remote to the one of interest. Doing so, he explained, can either pro­mote or diminish the pri­mary receptor’s inter­ac­tion with the endoge­nous com­pounds. So, his marijuana-​​like drugs bind to a remote receptor and sub­se­quently cause CB1 to bind endocannabinoids–which are like nat­u­rally occur­ring THC molecules–in either greater or smaller amounts. The result are drugs that can treat things like anorexia ner­vosa (by pro­moting the desire to eat), obe­sity (by depressing that desire), glau­coma (by decreasing intraoc­ular pres­sure) and PTSD (by pro­moting the blissful feeling that comes with smoking dope), without the neg­a­tive side effects of addic­tion and impaired memory.

But in his work on the α7 receptor, he’s devel­oping an entirely new class of com­pounds that work a little dif­fer­ently. In the former examples–which are called PAMs (or NAMs), for pos­i­tive (or neg­a­tive) allosteric modulators–the process depends on a good supply of the endoge­nous compound.

Thakur is an assis­tant pro­fessor of phar­ma­ceu­tical sci­ences and a fac­ulty fellow in the Center for Drug Dis­covery. Photo by Brooks Canaday.

But what if there is no endoge­nous com­pound, or there isn’t enough of it around to have much of an effect?

The new mol­e­cules Thakur is working on are called ago-​​PAMs. The “ago” stands for ago­nist, and it basi­cally refers to the fact that these com­pounds can pro­mote the ben­e­fits expe­ri­enced by binding of endoge­nous lig­ands to the pri­mary receptor without having to actu­ally do so. It binds to a remote (or “allosteric”) site on the receptor rather than the endoge­nous mol­e­cule binding site on α7, thus it’s still tech­ni­cally a PAM.

In a paper released on Valentine’s Day (fit­tingly, since Thakur is clearly in love with this sub­ject) in the Journal of Bio­log­ical Chem­istry, he and his team pre­sented a detailed account of the struc­ture of the allosteric binding site of α7 nico­tinic acetyl­choline receptor where such ago-​​PAM com­pounds sits on. This is impor­tant because without knowing what that pro­tein binding site looks like, it’s hard to make things that bind to it perfectly.

“This finding,” said Thakur, “is going to help us develop more potent and effi­ca­cious com­pounds as memory and cog­ni­tion enhancers, addic­tion treat­ment, and for treat­ment of neu­ro­pathic pain.”

Indeed, he’s already had some promising results on the memory and cog­ni­tion front, thanks to a col­lab­o­ra­tive pilot research project with Jonghan Kim, a fellow assis­tant pro­fessor in the School of Pharmacy.

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About the Writer

Angela Herring is the science writer for the Northeastern news team. In a past life, she made fullerenes (aka bucky balls) at a small chemical company outside of Boston while freelance writing for the Harvard Stem Cell Institute, the Broad Institute and Novartis Biomedical Research Institutes. She earned her Bachelor's degree in chemistry and literature from Bennington College in 2005. In addition to writing stories for the News@Northeastern, she also maintains the university's research blog: iNSolution.

2 comments

I really appre­ciate arti­cles like these that simply explore and explain cur­rent research that people out­side these fields might oth­er­wise never hear about. Your expla­na­tions are clear and under­stand­able, and the research seems quite inno­v­a­tive. I like to hear about sci­en­tists who think so cre­atively, and I espe­cially like the idea that they are looking to take advan­tage of the brain’s propen­sity for feeling good, rather than looking to sup­press it. Looking for­ward to more good things from these folks!

Agreed, well done. Regarding these com­pounds applied to replacing/​blocking the phys­i­o­log­ical need for some addic­tive sub­stances, wouldn’t the psy­cho­log­ical risks, depen­dence increase? I get the ben­e­fits, and think addressing the mental effects would be valu­able as well. Great piece.

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